The irradiated brain tumor microenvironment: Biology and therapeutic targets

Gliomas are the most common brain tumors and the highest-grade glioma, glioblastoma (GBM), is arguably the deadliest and most aggressive tumor type, with no long-term survivors and a median survival of just 8-12 months. Patients with GBM are treated with radiotherapy, chemotherapy, surgery and tumor treating fields.

Despite initial response all tumors recur as incurable lesions.

Recent advances have established a central role for the tumor microenvironment in determining the therapeutic response of GBM cells, and our lab demonstrated that standard of care radiotherapy of the primary tumor can shape the microenvironment to generate tumor-supportive conditions and therapeutic resistance in the recurrent tumor.

By integrating single cell RNA sequencing data, multiplexed immunohistochemistry, and spatial transcriptomics from state-of-the-art experimental models, we aim to consolidate the contribution of the irradiated brain tumor microenvironment to GBM resistance, with the ultimate goal of exploiting recently identified and novel therapeutic opportunities unique to the irradiated brain.

We further intend to screen for candidate drugs to reverse the tumor-supportive effect of the stromal astrocytic response to radiotherapy, ultimately aiming to sensitize resistant brain tumor cells to the standard of care.

With 200,000 people succumbing to brain tumors annually, there is an urgent need for a better understanding of therapeutic resistance and novel therapeutic strategies.